Aminotetralin derivative for the therapy of cardiovascular diseases

ABSTRACT

A method of treating congestive heart failure is diclosed comprising administering 5,6-dihydroxy- or 5,6-diisobutyroyloxy-2-methylaminotetralin or a pharmaceutically acceptable salt thereof.

This application is a 371 of PCT/EP96/01060 filed Mar. 13, 1996

The present invention relates to the use of5,6-diisobutyroyloxy-2-methylaminotetralin in the preparation ofpharmaceutical compositions for the therapy of cardiac disorders,particularly congestive heart failure.

Notwithstanding the therapeutical progresses of the last years,congestive heart failure is still one of the main death causes.

The symptomatic therapy usually aims at reducing the workload of thedecompensed heart and improving the mechanical function.

Recently, cardiac failure was proved to be related with importantbiochemical and neurohumoral changes involving different factors.

In fact, when cardiac output diminishes, compensatory mechanisms act inthe body in order to maintain the circulatory homeostasis.

In heart failure, vasoconstriction associated with the activation ofsaid mechanisms cause an increase in peripheral vascular resistances.

As a consequence, the after-load increases which can in turn furtherstrain the already weakened heart, triggering a vicious circle whichleads to a progress of the pathology.

This generalized vasoconstriction is mainly caused by the activation ofthe sympathetic nervous system consequent to the increase of plasmacatecholamines, particularly adrenalin, which is an early signal ofcardiac decompensation.

A close relationship between degree of sympathetic activation andseverity of the disease seems to exist, and a direct connection betweennoradrenalin plasmatic levels and mortality seems moreover established.

Therefore, the therapy of congestive heart failure has to be directed tothe improvement of the hemodynamic factors, on one hand, and to thepharmacological modulation of the neurohumoral system on the other.

Dopaminergic drugs appear as candidates to become established as drugsfor heart failure in the majority of patients.

In particular, dopamine has peculiar characteristics, compared with theother medicaments, since it stimulates both dopaminergic and alpha andbeta-adrenergic receptors.

Two types of dopaminergic receptors exist: those located on the smoothmuscle of the vascular system (DA₁ receptors) which mediate vasodilationin the renal, mesenteric, cerebral and coronary districts, and those inpre-synaptic position (DA₂ receptors), which inhibit noradrenalinrelease from post-ganglionic sympathetic nerve endings to blood vesselsand heart.

The usefulness of dopamine in the treatment of heart failure is howeverrestricted by it being inactive orally.

Analogously dobutamine, a synthetic analogue of dopamine, can be usedonly intravenously.

Aminotetralin derivatives have been studied for a long time as dopaminestructural analogues for any uses as medicaments.

However, none of these compounds has up to now been introduced intherapy.

One of them, 5,6-dihydroxy 2-methylaminotetralin hydrobromide, wasdisclosed as coronary vasodilator in the U.S. Pat. No. 4,134,997 in thename of Joseph G. Cannon.

Cannon administered the compound to dogs at a rate of approximately 10μg/kg animal weight per minute (rante 8.5-13.9) by a continuousintravenous infusion and demonstrated a substantial increase in coronaryblood flow.

5,6-Diisobutyroyloxy-2-methylaminotetralin, herein-after referred to asCHF 1035, has been described first in GB Pat. 2123410 among a series ofaminotetralin derivatives disclosed as potential antibronchospastic dueto their activity on adrenergic receptors.

Both 5,6-dihydroxy-2-methylaminotetralin (herein-after indicated withthe experimental abbreviation CHF 1024) and CHF 1035 have been formerlycharacterized as compounds having previling selective activity on β₂adrenergic receptors.

Now it has been surprisingly found that CHF 1024 and CHF 1035, inaddition to the already known β₂ agonist activity, have remarkableperipheral DA₂ and α₂ presynaptic activities leading to a reduction ofthe sympathetic tone, which is elevated in heart failure patients.

Studies carried out in the animal proved that CHF 1024 and CHF 1035 havea vasodilating activity due the combination of their effects on α₂, β₂and DA₁ /DA₂ receptors as well as a cardiac inotropic activity.

They are effective at a very low doses, even by oral route.

The peripheral α₂ adrenergic and peripheral DA₂ dopaminergic activitiesof the aminotetralin derivatives of the present invention have neverbeen described until now.

On the contrary, it was previously affirmed by Hilditch A. and Drew G.M. in European Journal of Pharmacology, vol. 72, pages 287-296, 1981that the compound 5,6-dihydroxy 2-methylaminotetralin was inactive asdopamine receptor agonist in relaxing the splenic artery strips.

We have demonstrated that both CHF 1024 and CHF 1035 have agonistactivity on dopaminergic receptors and that they are selective for thepresynaptic DA₂ ones.

The α₂ adrenergic and DA₂ -dopaminergic activities of the compounds havebeen evaluated in binding tests (example 1 and 3), in isolatedneuronally-stimulated rat vas deferens (example 2) and in rabbitrectococcygeus muscle (example 4).

The cardiovascular effects of the compounds have been evaluated in vivoin anesthetized rats both after intravenous and intraduodenaladministration (example 5).

EXAMPLE 1

The affinity of CHF 1024 and CHF 1035 for α₂ adrenergic receptors wastested on human platelets and on rat cerebral cortex.

The antagonist [³ H]-rauwolscine was used as marker of the receptor,being its binding reversible, saturable and specific.

CHF 1024 exhibited a significantly higher affinity than dopamine, 9times in platelets and 15 times in cerebral cortex. The affinity of CHF1035 was similar to that of dopamine, utilized as reference compound.

The lower affinity of CHF 1035 for the receptor is probably due to theesterification of the molecule.

    ______________________________________                                                  CHF 1024 CHF 1035   DOPAMINE                                        ______________________________________                                        human platelets                                                                           3.39 × 10.sup.-7                                                                   2.70 × 10.sup.-6                                                                   3.04 × 10.sup.-6                         (±0.13) (±0.45) (±0.38)                                             rat cerebral 2.62 × 10.sup.-7 2.65 × 10.sup.-6 4.06 ×                                       10.sup.-6                                     cortex (±0.58) (±0.67) (±0.97)                                     ______________________________________                                    

Values are expressed as IC₅₀ =molar concentration of drug required for50% inhibition of [³ H]-rauwolscine specific binding.

EXAMPLE 2

The α₂ -adrenergic activity of the aminotetraline derivatives CHF 1024and CHF 1035 has been evaluated in isolated neuronally-stimulated ratvas deferens in comparison with dopamine.

The results are expressed in the following table as IC₅₀ value=molarconcentration of drug which induces 50% inhibition of the electricallyinduced contraction:

    ______________________________________                                                CHF 1024  CHF 1035   DOPAMINE                                         ______________________________________                                        IC.sub.50 (M)                                                                           2.70 × 10.sup.-7                                                                    7.14 × 10.sup.-8                                                                   4.91 × 10.sup.-6                         C.I. 2.15-3.38 5.63-9.05 4.19-5.75                                          ______________________________________                                         C.I. = 95% Confidence Interval                                           

The compounds CHF 1024 and CHF 1035 resulted about 20 and 70 times morepotent that dopamine, respectively.

EXAMPLE 3 Peripheral DA₂ Dopaminergic Activity (Binding test)

The affinity of CHF 1024 for peripheral DA₂ dopaminergic receptors wastested on bovine adrenal cortex evaluating its effect on the interactionof [³ H]-(-)sulpiride with the specific binding sites of this system.

Dopamine has been employed as reference compound.

The results, expressed as IC₅₀ (molar concentration required for 50%inhibition of specific binding) are reported herebelow.

    ______________________________________                                                      CHF 1024   DOPAMINE                                             ______________________________________                                        Bovine adrenal cortex                                                                         2.1 × 10.sup.-8                                                                      2.3 × 10.sup.-7                              [.sup.3 H]-sulpiride                                                        ______________________________________                                    

The affinity of CHF 1024 for DA₂ receptors is 11 times higher than thatof dopamine.

EXAMPLE 4 Peripheral DA₂ Dopaminergic Activity (in Vitro Test)

The activity of CHF 1024 and CHF 1035 on peripheral DA₂ dopaminergicreceptors has been tested in the electrically stimulated rabbitrectococcygeus muscle.

Both compounds determined a dose-dependent inhibition of contractioninduced by electrical stimulation and were approximately 3 times morepotent than dopamine, utilized as reference compound.

In the table below the IC₅₀ values (molar concentration of drug whichinduces 50% inhibition of the electrically induced contraction) arereported:

    ______________________________________                                                CHF 1024  CHF 1035   DOPAMINE                                         ______________________________________                                        IC.sub.50 (M)                                                                           3.73 × 10.sup.-8                                                                    2.96 × 10.sup.-8                                                                   9.93 × 10.sup.-8                         C.I. 3.16-4.36 2.14-3.88 4.79-18.21                                         ______________________________________                                    

(95% Confidence Interval)

The effects produced by CHF 1024, CHF 1035 and dopamine werecompetitively antagonized by the selective DA₂ -antagonist domperidone.

EXAMPLE 5 In vivo Cardiovascular Effects

Male albino rats (Sprague Dawley, 350-400 g) were anesthetized by sodiumpentobarbital (60 mg/kg) and maintained by i.v. infusion (6 mg/h). Thetrachea was cannulated to facilitate spontaneous respiration and bodytemperature was maintained at 37° C. Homoeothermic Blanket ControlSystem (Harvard, England).

The right femoral artery was cannulated for arterial blood pressuremeasurement and left jugular vein or duodenum were cannulated for drugadministration. Mean arterial pressure and heart rate were continuouslymonitored by pressure transducer and medium gain amplifier triggered bythe ECG signal, respectively.

After a stabilization period of about 15 min, CHF 1024 (0.23, 0.69 and2.3 μg/kg/min) was administered by intravenous infusion for 30 min andcardiovascular parameters were recorded for further 30 min afterdiscontinuation.

CHF 1035 was administered intraduodenally (1 mg/kg).

The response to CHF 1035 was determined in the absence and in thepresence of the selective β₂ -adrenoceptor antagonist ICI 118.551 (0.2mg/kg i.v.) and the selective DA₂ -dopaminergic antagonist domperidone(0.3 mg/kg i.v.) both alone and in combination. The antagonists wereadministered 10 min before the i.d. drug administration.

Intravenous administration of CHF 1024 induced a dose-dependentreduction in mean arterial pressure which persists even after infusiondiscontinuation.

Effects induced by intravenous infusion of the compound on mean arterialpressure in anesthetized rat. Mean±s.e.m. values (expressed as changesfrom basal value) are reported.

    __________________________________________________________________________                 min after infusion                                                                         min after infusion                                    μg/kg/min  start stop                                                    i.v.       n 5      30    5      30                                           __________________________________________________________________________    VEHICLE                                                                             --   7  1.7 ± 2.0                                                                         3.7 ± 2.9                                                                        4.0 ± 2.2                                                                         2.0 ± 2.4                                  CHF 1024 0.23 6  -6.3 ± 2.1 -13.7 ± 4.2  -8.3 ± 3.4 -8.0 ±                                       3.3                                             0.69 6 -24.0 ± 3.8 -25.7 ± 5.4 -12.7 ± 5.2 -6.7 ± 3.3                                             2.3  6 -47.7 ± 7.4 -48.7 ± 5.7                                        -34.0 ± 6.3 -25.3 ± 7.1                __________________________________________________________________________     n = number of animals                                                    

In spite of marked hypotension, no increase in heart rate was observed.

Analogously, intraduodenal administration of CHF 1035 at 1 mg/kgmarkedly reduced blood pressure without affecting heart rate.

The hypotensive response was characterized by a rapid and marked fall(peak effect of about 45% reduction from basal value at 5 min afteradministration) followed by a slow recovery (about 20% reduction frombasal value is still present 2 hours after administration).

It has been shown that the peak effect is significantly reduced bypretreatment with the β₂ -antagonist, while DA₂ -antagonistsignificantly shortened the hypotensive response (the basal value iscompletely recovered 60 min from administration). The administration ofboth antagonists combined completely abolished the hypotensive response.

It has been so demonstrated that the compound is active at dosesconsiderably lower than those described by Cannon and that both β₂-adrenergic and DA₂ -dopaminergic receptors are involved in thehypotensive activity.

In particular the DA₂ stimulation seems to be responsible of thelong-lasting activity of the compound.

In order to investigate the effects of the compound both on thehemodynamic parameters and the neurohumoral pattern, a randomizeddouble-blind study versus placebo was carried out in 18 patients with amoderate congestive heart failure (class NYHA II-III).

Each patient received on 3 consecutive days 2 active doses of CHF 1035and 1 placebo dose.

The following hemodynamic parameters were evaluated:

pulmonary capillary wedge pressure (PCWP) (mmHg);

cardiac index (CT) (L/min/m²);

stroke volume index (SVI) (ml/min/m²);

systemic vascular resistance (SVR) (dyneseccm⁻⁵);

heart rate (HR) (bpm);

mean blood pressure (BPm) (mmHg).

The evaluations were carried out by catheterization of the right heart(Swan-Ganz catheter), measuring the hemodynamic parameters of the testedmedicament before administration or "pre-dose" (PD) and for the 300subsequent minutes after the administration or "after-dose" (AD), every20 minutes for the first 2 hours, then every 60 minutes.

To evaluate the effects of the compound on neurohormones, noradrenalin(NE) (pg/ml) and adrenalin (E) (pg/ml) plasmatic levels were furtherevaluated, before and 140 minutes after the administration of CHF 1035and placebo, respectively.

The administration of CHF 1035 at the 3 dose levels, induced changes inthe hemodynamic and neurohumoral parameters as shown in the followingtable:

                                      TABLE                                       __________________________________________________________________________    5 mg            10 mg       15 mg                                             PD        AD    PD    AD    PD    AD                                          __________________________________________________________________________    PCWP                                                                              22 ± 5                                                                           18 ± 4*                                                                          20 ± 6                                                                           16 ± 9*                                                                          21 ± 7                                                                           16 ± 6*                                    CI 3 ± 1 3,4 ± 1*  2,7 ± 1   3,4 ± 1*  3 ± 1 4 ± 1*                                          SVI 39 ± 12 43 ± 11 38 ± 7                                          45 ± 10* 40 ± 10 49 ± 11*                                             SVR 1243 ± 27  1052 ± 265* 1382                                        ± 45  1009 ± 315* 1359 ± 36                                          881 ± 257*                                 HR 74 ± 11  78 ± 11* 70 ± 11 76 ± 12 74 ± 12 80 ± 10*       BPm 85 ± 12 82 ± 12 85 ± 10  77 ± 13* 87 ± 11 79 ±                                          12*                                           NE 299 ± 135 301 ± 156 285 ± 244 244 ± 88* 340 ± 162 308                                       ± 133                                      E 56 ± 29  42 ± 21* 65 ± 42 62 ± 44 53 ± 25 58 ± 24       __________________________________________________________________________     *p < 0.05                                                                

On the contrary, the administration of placebo induced no changes in thesame parameters.

The results prove that CHF 1035, at the doses used in the study, inducesa significant improvement in hemodynamic parameters and is characterizedby a particularly favourable pharmacological profile.

Whilst a dose-related reduction in the peripheral vascular resistancesis observed (respectively -15.4%; -27.0%; -35.2% for the 3 dose levels),only a relative increase in heart rate occurs, which is not clinicallysignificant.

The reduction in ventricular after-load, which is the expression of thedecrease in the peripheral vascular resistances, induces a significantincrease in the cardiac index.

Moreover the significant reduction in the pulmonary capillary wedgepressure should be stressed, which means that the medicament alsoinduces venous vasodilation, with a consequent reduction in the leftventricle pre-load.

Therefore, the general hemodynamic effect CHF 1035 can be ascribed tothe peripheral vasodilating activity of the medicament, both arterialand venous.

This evident activity on peripheral receptors could have induced aneurohumoral hyper-reactivity, with a consequent increase innoradrenalin and adrenalin plasmatic levels, which is an undesiredreaction in a pathological subject.

On the contrary, the results reported above prove that CHF 1035 iscapable of inducing systemic vasodilation without inducing any reflectedincrease in catecholamines plasmatic levels.

The vasodilating activity of the compound derives from its receptorproperties, particularly from the activity on pre-synaptic DA₂ and α₂receptors, the stimulation of which can inhibit the catecholaminerelease, as it is well known.

As said before, congestive heart failure is one of the most commoncauses of death and disability in industrialized nations and is amongthe syndromes most commonly encountered in clinical practice, affectingnearly 4 millions persons in the USA and 14 millions individuals inEurope.

The current pharmacological treatment of the condition includesdiuretics, angiotensin converting enzyme (ACE) inhibitors and digitalis.

There is a strong impression among the experts that the pharmacologictreatment of patients with heart failure remains suboptimal and moreeffective treatment is required to prevent complications and therebyreduce morbidity and mortality.

It has been demonstrated that CHF 1035 improves the clinical conditionand the exercise capacity of patients with congestive heart failure whenused as add-on therapy to baseline therapy with diuretics or withdiuretics and ACE-inhibitors and/or with diuretics and digitalis.

It has also been shown that the pharmacodynamic effects last longer thandetectable serum levels of the drug. The time course of these effects isindependent of the kinetics of the drug in the body.

The effects of CHF 1035 as added therapy have been evaluated in patientssuffering from NYHA class II-III congestive heart failure due to mildhypertension, or coronary disease, or chronic cardiomyopathy, who wereon diuretics or diuretics and an angiotensin-converting enzymeinhibitor.

Recruited patients were randomly assigned to added double-blindtreatment with placebo or with three different doses of the study drug(5 mg, 10 mg, 15 mg).

The study therapy was started by patients on day 1 and proceeded untilday 28 of the study.

The following parameters have been considered to determine the clinicalcondition of patients:

pulmonary congestion;

systemic congestion;

central haemodynamics;

regional blood flows

The functional response to the treatments has been evaluated byexertional tests, the 6-minute walking test and the 130-meter walkingtest.

CHF 1035 improved the functional and clinical condition of patients,compared to placebo.

This improvement was ostensible in terms of the NYHA functional class,exercise performance, and symptoms and signs of pulmonary and systemiccongestion, central haemodynamic, alterations, and decreasedregional/organ blood flows.

For the evaluation of clinical condition, more than 60 symptoms or signswere evaluated.

For statistical purposes scores from signs and symptoms (as applicable)were summed to form clinical compound scorings (CCSs) ofpathophysiological importance in congestive heart failure.

Three CCSs were evaluated by adding the scores for certain symptoms andsigns; each symptom and sign was used for only one CCS. The centralhemodynamics (CH, 0-17), the pulmonary congestion (PC, 0-26), and thesystemic congestion (SC, 0-8) CCS were associated with the NYHAfunctional class (p=0.013; p=0.001; p=0.001) before, and they correlatedwith it positively (p=0.001; p=0.022; p<0.001) after CHF 1035 add-ontherapy.

The pulmonary congestion CCS correlated also with the 130-m mean walkingvelocity (p=0.002/p=0.035) and with the left ventricle end-diastolic(p=0.026/p=0.019) and end-systolic internal dimensions before/after CHF1035 add-on therapy.

The pulmonary congestion appeared as the most important determinant ofthe functional status in congestive heart failure and was the mostsensitive CCS to CHF 1035 add-on therapy.

Furthermore, pharmacological and clinicopharmacological studies showedthat CHF 1035 increases diuresis without affect natriuresis andkaliuresis.

CHF 1035 is the diisobutyroyl ester of5,6-dihydroxy-2-methylaminotetralin, which is referred to as CHF 1024.

Immediately after the administration, CHF 103.5 is transformed by theplasma and tissue esterases into the pharmacologically activedesesterified form, which is also included within the present invention.

Due to these favorable characteristics, CHF 1035 can be advantageouslyused as pro-drug for the preparation of pharmaceutical compositions forthe therapy of cardiac disorders and in particular of the congestivecardiac failure.

The daily dose of the active ingredient can vary from 1 to 100 mg andpreferably will range from 2.5 to 20 mg.

The administration can be performed by any route, preferably by the oralroute.

For the oral administration, the compound can be formulated in solid orliquid preparations, preferably in tablets, using the additives andexcipients of common use in pharmaceutical technique.

Another particularly advantageous method for the administration of thecompound of the invention are the transdermal systems, which areadhesive matrixes that can be applied to the skin containing a suitableconcentration of the active ingredient, which can gradually be releasedthus entering the blood circulation.

We claim:
 1. A method of treating congestive heart failure,comprising:administering to a subject suffering from said disorder atherapeutically effective amount of5,6-diisobutyroyloxy-2-methylaminotetralin or a pharmaceuticallyacceptable salt thereof.
 2. The method of claim 1, wherein a dailydosage of 5,6-diisobutyroyloxy-2-methylaminotetralin is administered ina range of 1 to 100 mg per day.
 3. The method according to claim 2,wherein said daily dosage range is 2.5 to 20 mg.
 4. The method accordingto claim 1, wherein said active ingredient is administeredtransdermally.
 5. The method according to claim 1, wherein said activeingredient is administered orally.
 6. A method of treating congestiveheart failure, comprisingadministering to a subject suffering from saiddisorder a therapeutically effective amount of5,6-dihydroxy-2-methylaminotetralin or a pharmaceutically acceptablesalt thereof.
 7. The method of claim 6, wherein said5,6-dihydroxy-2-methylaminotetralin is administered in a daily dose of 1to 100 mg.
 8. A method of treating congestive heart failurecomprisingadministering to a subject suffering from said disordertherapeutically effective amounts of5,6-diisobutyroyloxy-2-methylaminotetralin or a pharmaceuticallyacceptable salt thereof and a diuretic.
 9. A method of treatingcongestive heart failure, comprisingadministering to a subject sufferingfrom said disorder therapeutically effective amounts of5,6-diisobutyroyloxy-2-methylaminotetralin or a pharmaceuticallyacceptable salt thereof and a diuretic and an ACE inhibitor.
 10. Amethod of treating congestive heart failure, comprisingadministering toa subject suffering from said disorder a single therapeuticallyeffective dose of 5,6-diisobutyroyloxy-2-methylaminotetralin or apharmaceutically acceptable salt thereof.